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Wnt/β‐catenin signaling, but not AKT/β‐catenin signaling is required for epithelial restitution following colitis
Author(s) -
Koch Stefan,
Nava Porfirio,
Parkos Charles A,
Nusrat Asma
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.348.8
Subject(s) - dkk1 , wnt signaling pathway , protein kinase b , colitis , pi3k/akt/mtor pathway , cancer research , catenin , inflammatory bowel disease , cytokine , downregulation and upregulation , intestinal mucosa , signal transduction , medicine , immunology , chemistry , biology , microbiology and biotechnology , disease , biochemistry , gene
We and others have previously shown that inflammatory cytokine induce the production of the secreted Wnt signaling antagonist Dkk1. Since elevated cytokine levels in the intestinal mucosa are a hallmark of inflammatory disorders of the intestine, we evaluated the contribution of this Wnt inhibitor to the pathogenesis of chronic colitis using Dkk1 hypomorphic doubleridge mice, and anti‐Dkk1 antibody treatment in vivo and in vitro. Dkk1 hypomorphic animals showed a significantly faster recovery from experimental colitis as assessed by a combined disease activity score and histological examination, which coincided with increased LRP6 levels in intestinal epithelial cells and increased PI3K activity. Conversely, AKT protein levels and activity, and subsequent AKT‐mediated β‐catenin phosphorylation were decreased in doubleridge mice during acute colitis. Downregulation of AKT in the absence of Dkk1 was confirmed by extended treatment of model intestinal epithelial cell lines with anti‐Dkk1 antibody. These results suggest that Wnt/β‐catenin, but not AKT/β‐catenin signaling is required for the recovery from inflammatory epithelial injury. Supported by grants from the National Institutes of Health (DK72564, DK61379 and DK79392 to C.A.P., DK53202, DK55679, DK59888 to A.N.), and the Crohn's & Colitis Foundation of America (to S.K. and P.N.).